The present invention relates to the field of macrolide compounds having antibacterial activity, pharmaceutical compositions containing the compounds, and methods of treating bacterial infections with the compounds.
Erythromycins are well-known antibacterial agents widely used to treat and prevent bacterial infection caused by Gram-positive and Gram-negative bacteria. However, due to their low stability in acidic environment, they often carry side effects such as poor and erratic oral absorption. As with other antibacterial agents, bacterial strains having resistance or insufficient susceptibility to erythromycin have developed over time and are identified in patients suffering from such ailments as community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections. Particularly problematic pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and macrolide-resistant Streptococcus pneumoniae. Therefore, continuing efforts are called for to identify new erythromycin derivative compounds with improved antibacterial activity, and/or unanticipated selectivity against various target microorganisms, particularly erythromycin-resistant strains.
The following references relate to various erythromycin derivatives disclosed as having antibacterial activity:
EP 216,169 and U.S. Pat. No. 4,826,820 to Brain et al. disclose antibacterially active 6-carbamate erythromycin derivatives stated to xe2x80x9chave antibacterial properties, in particular against Gram-positive bacteria but also against some Gram-negative bacteria.xe2x80x9d
U.S. Pat. Nos. 5,444,051, 5,561,118, and 5,770,579, all to Agouridas et al., disclose erythromycin compounds such as those of the formulae 
wherein substituents are as described in the respective references, which are all stated to be useful as antibiotics.
U.S. Pat. No. 5,866,549 to Or et al. and WO 98/09978 (Or et al.) disclose 6-O-substituted ketolides stated to have increased acid stability relative to erythromycin A and 6-O-methyl erythromycin A and enhanced activity toward gram negative bacteria and macrolide resistant gram positive bacteria.
WO 97/17356 (Or et al.) discloses tricyclic erythromycin derivatives stated to be useful in the treatment and prevention of bacterial infections.
WO 99/21871 (Phan et al.) discloses 2-halo-6-O-substituted ketolide derivatives of the formula 
wherein substituents are as described in the respective reference, which are stated to possess antibacterial activity.
WO 99/21864 (Or et al.) discloses 6,11-bridged erythromycin derivatives having antibacterial activity.
WO 00/75156 (Phan et al.) discloses 6-O-carbamate ketolide derivatives that are useful as antibacterial agents for the treatment and prevention of infection in a mammal.
EP1146051 to Kaneko et al. discloses macrolide compounds of the following formula that are useful as antibacterial and antiprotozoal agents in mammals, 
wherein substituents are as described in the reference.
EP1114826 to Kaneko and McMillen discloses novel erythromycin derivatives useful as antibacterial, antiprotozoal and/or prokinetic agents.
WO 00/71557 to Dirlam et al. discloses 13-methyl-erythromycin derivatives that are useful as antibacterial and antiprotozoal agents in mammals (including humans), fish and birds.
U.S. Pat. No. 6,355,620 to Ma et al. discloses C-2 modified erythromycin derivatives that are useful in treating bacterial infections.
WO 02/032918 to Hlasta et al. discloses a series of erythromycin ketolides that possess anti-infective activity and are useful for the treatment of bacterial and protozoal infections.
WO 00/062783 to Hlasta et al. discloses erythromycin analogs useful in the treatment of bacterial and protozoal infections and in the treatment of other conditions involving gastric motility.
U.S. Pat. No. 5,922,683 to Or et al. discloses multicyclic erythromycin compounds having antibacterial activity.
U.S. Pat. No. 6,034,069 to Or et al. discloses 3xe2x80x2-N-modified 6-O-substituted erythromycin ketolide compounds having antibacterial activity.
The invention provides compounds of Formula 1: 
wherein
R1 is selected from the group consisting of hydrogen, halogen, and hydroxy;
Z is selected from the group consisting of xe2x80x94NHxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94NHxe2x80x94C1-C6alkenyl-, xe2x80x94C1-C6alkenyl-, xe2x80x94Oxe2x80x94C1-C6alkenyl-, NHC1xe2x80x94C6alkynyl-, xe2x80x94C1-C6alkynyl-, and xe2x80x94Oxe2x80x94C1-C6alkynyl-, wherein n is an integer from 0 to 5;
R2 is selected from the group consisting of hydrogen, aryl, and heteroaryl;
R3 is selected from the group consisting of hydrogen, C1-C10alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl, C3-C6-cycloalkyl, C5-C8-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;
R4 is hydrogen or a hydroxy protecting group;
W is selected from the group consisting of
(1) a substituted pyrrole of the formula 
xe2x80x83wherein
R5 and R6 are independently selected from the group consisting of hydrogen, CN, xe2x80x94C(NH)CHR10R11, nitro, xe2x80x94C(O)R7, xe2x80x94C(O)OR7, xe2x80x94C(O)NR7R8, xe2x80x94SO2R7, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl, wherein
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; and
R10 and R11 are independently selected from the group consisting of hydrogen, C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl, or R10 and R11, taken together with the atoms to which they are attached, form an optionally substituted 4-8 membered carbocyclic ring wherein the substituents are selected from the group consisting of C0-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, aryl, and heteroaryl;
(2)xe2x80x94OR9, wherein
R9 is independently selected from the group consisting of C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, and C5-C8-cycloalkenyl;
(3) xe2x80x94NR10OR11, wherein
R10 and R11 are independently selected from the group consisting of hydrogen, C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl, or R10 and R11, taken together with the atoms to which they are attached, form an optionally substituted 5-8 membered heterocyclic ring wherein the substituents are selected from the group consisting of C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, aryl, and heteroaryl;
(4) xe2x80x94NR12NR13R14, wherein
R12, R13, and R14 are independently selected from the group consisting of hydrogen, C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl,
or R12 and R13, taken together with the nitrogens to which they are attached, form an optionally substituted 5-8 membered heterocyclic ring, wherein the substituents are selected from the group consisting of C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, aryl, and heteroaryl;
or R13 and R14, taken together with the nitrogen to which they are attached, form an optionally substituted 3-8 membered heterocyclic ring or an optionally substituted 5-10 membered heteroaryl ring, wherein the substituents are selected from the group consisting of C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, aryl, and heteroaryl;
(5) xe2x80x94NR5Nxe2x95x90CHR13a, wherein
R15 is independently selected from the group consisting of hydrogen, C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl; and
R13a is independently selected from the group consisting of C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl;
(6) xe2x80x94NR10NR11C(O)R16, wherein
R16 is independently selected from the group consisting of hydrogen, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl;
(7) xe2x80x94NR10NR11C(O)OR17, wherein
R17 is independently selected from the group consisting of C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl;
(8) xe2x80x94NR10NR11C(O)NR18R19, wherein
R18 and R19 are independently selected from the group consisting of hydrogen, C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl, or R18 and R19, taken together with the nitrogen to which they are attached, form an optionally substituted 3-8 membered heterocyclic ring or an optionally substituted 5-10 membered heteroaryl ring, wherein the substituents are selected from the group consisting of C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, aryl, and heteroaryl;
(9) xe2x80x94NR10NR21SO2R20, wherein
R20 is independently selected from the group consisting of C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl; and
R21 is independently selected from the group consisting of hydrogen, C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, C2-C6 acyl, aryl, and heteroaryl;
(10) xe2x80x94SR9, wherein
R9 is independently selected from the group consisting of C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, and C5-C8-cycloalkenyl;
(11) xe2x80x94CHR10R11, wherein
R10 and R11 are independently selected from the group consisting of hydrogen, C1-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl, or R10 and R11, taken together with the atoms to which they are attached, form an optionally substituted 4-8 membered carbocyclic ring wherein the substituents are selected from the group consisting of C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, aryl, and heteroaryl; and
(12) a substituted pyrazole of the formula 
xe2x80x83wherein
R22 and R23 are independently selected from the group consisting of hydrogen, xe2x80x94C(O)OR7, xe2x80x94C(O)NR7R8, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, aryl, and heteroaryl, wherein
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl;
X and Xxe2x80x2, together with the carbon atom to which they are attached, form Cxe2x95x90O, Cxe2x95x90NRc, or Cxe2x95x90NORc, wherein Rc is independently selected from hydrogen, alkyl, alkenyl and alkynyl; and
Y and Yxe2x80x2, together with the carbon atom to which they are attached, form Cxe2x95x90O, xe2x80x94CHOH, Cxe2x95x90NRc, or Cxe2x95x90NORc, wherein Rc is independently selected from hydrogen, alkyl, alkenyl and alkynyl;
or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, esters or pro-drugs thereof.
Compounds of the above formula are useful as antibacterial agents for the treatment of bacterial infections in a subject such as human and animal.
The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula 1.
The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective amount of the compound of Formula 1.
Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.